We propose using ultra low dose Interleukin 2 (ULD-IL2) to reduce the risk of Graft versus host disease after allogeneic hematopoietic stem cell transplantation (Allo SCT) by increasing levels of endogenous T regulatory cells. AlloSCT) is recognized as the treatment of choice for several hematologic malignancies, as well as for selected immunologic and genetic diseases. However, graft-versus-host disease (GvHD) is one of the major adverse consequences of the procedure. GvHD occurs in approximately 30 to 70% of patients undergoing alloSCT increasing morbidity and mortality, as well as the cost of care. Standard prophylactic therapies are often ineffective and may lead to significant complications. Including organ damage and impaired immune recovery with resultant life-threatening infections and an increased risk of relapse. Thus, more effective and less toxic therapies are needed to prevent GvHD post transplant, while still allowing for immune reconstitution post SCT. There has been increasing interest in the ability of regulatory T cells (Tregs) to modulate GvHD. Evidence suggests that alloSCT recipients with GvHD have lower absolute numbers of Tregs, while murine models have shown that infusion of donor Tregs post SCT prevents GvHD while maintaining the graft-versus- leukemia (GvL) effect. Although ex vivo expansion of T regs and subsequent infusion may be possible, cost and complexity are high. Moreover, one of the most specific markers for Treg is FoxP3, a transcriptional regulator that cannot be used as a basis for separating viable T regs from within the CD25 population. Furthermore, it is unclear whether natural Tregs expanded in vitro will have the same in vivo immunological properties as thymic-derived regulatory T cells. We propose a novel strategy to prevent GvHD by expanding donor-derived Tregs in vivo using ULD IL-2 in patients after alloSCT. Our underlying hypotheses are that (i) regulatory T cells can be preferentially expanded in vivo following alloSCT by the administration of ULD IL-2 to recipients early post SCT, as a strategy to prevent GvHD while (ii) preserving humoral, innate and cell mediated immunity to microbial pathogens and to residual malignancy. These hypotheses, formulated from extensive preclinical data and pilot clinical observations will be tested in two specific aims: (1) In a phase I/II clinical trial, we will determine whether the administration of ULD IL-2 in patients post allogeneic stem cell transplantation is safe and increases Tregs in vivo;and (2) Whether IL-2 induced Tregs affect cellular and humoral immune responses against leukemia, viruses and bacteria as a marker for their effect on post transplant relapse and infection. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation can cure patients with hematologic malignancies. However, a major side effect of this procedure is graft versus host disease (GvHD). To prevent this complication, patients usually receive powerful immunosuppressive drugs which can cause life-threatening infections and may increase the risk of relapse. We will determine whether ultra low-dose IL-2 will increase Tregs and prevent GvHD, without increasing the risk of infection or relapse.